Notch and MAPK may be key players in repair of aging muscle tissue, according to study in EMBO Molecular Medicine.

Certain biochemical pathways have been linked to the aging of human muscle. By manipulating these pathways, researchers at the University of California, Berkeley, were able to turn back the clock on old human muscle, restoring its ability to repair and rebuild itself.

The scientists demonstrated that mitogen-activated protein kinase (MAPK) is an important positive regulator of notch receptor activity essential for human muscle repair. When levels of MAPK were experimentally inhibited, young human muscle was no longer able to regenerate. The reverse was true when the investigators cultured old human muscle in a solution where activation of MAPK had been forced. In that case, the regenerative ability of the old muscle was significantly enhanced, the team reports. The findings will be reported in the September 30 issue of EMBO Molecular Medicine.

“Our study shows that the ability of old human muscle to be maintained and repaired by muscle stem cells can be restored to youthful vigor given the right mix of biochemical signals,” explains Irina Conboy, Ph.D., head of the group conducting the study. “This provides promising new targets for forestalling the debilitating muscle atrophy that accompanies aging and perhaps other tissue degenerative disorders as well.”

Previous research led by Dr. Conboy in animal models revealed that the ability of adult stem cells to do their job of repairing and replacing damaged tissue is governed by the molecular signals they get from surrounding muscle tissue. He also found that those signals change with age in ways that preclude productive tissue repair. The researchers say that aging in mice is associated in part with the progressive decline of notch and increased levels of TGF-beta, which sets off a chain reaction when excessively activated that ultimately inhibits a cell’s ability to divide. This results in blocking the stem cells’ capacity to effectively rebuild the body. This study revealed that the same pathways are at play in human muscle.

The animal studies also showed that the regenerative function in old stem cells can be revived given the appropriate biochemical signals. It was not clear until this new study whether similar rules applied for humans.

Working in collaboration with Michael Kjaer, M.D., Ph.D., and his research group at the Institute of Sports Medicine and Centre of Healthy Aging at the University of Copenhagen in Denmark, the UC Berkeley researchers compared samples of muscle tissue from nearly 30 healthy men who participated in an exercise physiology study. The young subjects ranged from age 21 to 24 and averaged 22.6 years of age, while the old study participants averaged 71.3 years, with a span of 68 to 74 years of age.

Muscle biopsies were taken from the quadriceps of all the subjects at the beginning of the study. The men then had the leg from which the muscle tissue was taken immobilized in a cast for two weeks to simulate muscle atrophy. After the cast was removed, the study participants exercised with weights to regain muscle mass in their newly freed legs. Additional samples of muscle tissue for each subject were taken at three days and again at four weeks after cast removal and then sent to UC Berkeley for analysis. 

Researchers found that before the legs were immobilized, the adult stem cells responsible for muscle repair and regeneration were only half as numerous in the old muscle as they were in young tissue. That difference increased even more during the exercise phase, with younger tissue having four times more regenerative cells that were actively repairing worn tissue compared with the old muscle, in which muscle stem cells remained inactive. The researchers also observed that old muscle showed signs of inflammatory response and scar formation during immobility and again four weeks after the cast was removed.

It was then that the researchers examined the response of the human muscle to biochemical signals and elucidated the role of MAPK and notch. “Now we know that the MAPK pathway plays a key role in regulation and aging of human tissue regeneration,” says Michael Conboy, a researcher at UC Berkeley. “In practical terms, we now know that to enhance regeneration of old human muscle and restore tissue health, we can either target the MAPK or the notch pathways.”

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